A Set of Marginal and Alleged Senolytics Show No Meaningful Benefits in a Cell Study

Senolytic compounds are those that selectively destroy senescent cells. As the accumulation of senescent cells is one of the root causes of aging, and senescent cells contribute directly to many specific age-related diseases, there is some interest in the development of effective senolytics. As is the case for any field of medical development, however, there are as many marginal and possible senolytic drugs as there are useful and proven senolytic drugs. The size of effect, the nature of the side-effects, and the quality of the evidence all matter greatly - indeed, this is the whole of the point when looking at whether a particular compound is viable or not.

The researchers here report on a few of the marginals and the possibles, compared against navitoclax, and observed no useful effect in a cell study. This is useful confirmatory work, even through the outcome is to be expected based on past evidence, particularly for quercetin. That said, it is important to note that different types of senescent cell have been shown to have quite different degrees of vulnerability to various classes of senolytic. It isn't quite as straightforward as failure in one cell type disqualifying a potential senolytic completely, but more a consideration of the balance of evidence from multiple studies.

Senolytic drugs hold the perspective to specifically target senescent cells and thereby to rejuvenate tissues or organisms. Several compounds have been suggested to possess senolytic effects, including navitoclax (ABT-263), quercetin, danazol, and nicotinamide riboside. ABT-263 inhibits BCL-2 protein family members, which are crucial regulators of the apoptosis pathway. ABT-263 was shown to deplete senescent cells of human umbilical vein epithelial cells (HUVECs), fibroblasts, but not human primary pre-adipocytes. Danazol is a synthetic androgen with telomere elongating capacity, which has been used to target accelerated telomere attrition - a hallmark of aging and senescence. Quercetin is a proteasome activator with anti-oxidant properties that triggers apoptosis via the BCL-2 pathway. Nicotinamide riboside increases levels of nicotinamide adenine dinucleotide (NAD+). Aged mice supplemented with nicotinamide riboside revealed increased lifespan and rejuvenated muscle stem cells.

Primary cells undergo a limited number of divisions before entering the state of replicative senescence. The process of senescence induces changes in morphology, metabolism, secretory phenotype, and differentiation potential of cells, thereby having a significant impact on experimental outcomes and affecting their therapeutic potential. This applies particularly to mesenchymal stromal cells (MSCs), which raise high hopes in tissue engineering and are concurrently tested in a multitude of clinical trials. MSCs comprise a multipotent subset of cells, capable of differentiation towards osteogenic, chondrogenic, and adipogenic lineages. The selective removal of senescent MSCs from cultures might improve standardization and effectiveness of cell preparations for cell therapeutics in regenerative medicine. We have therefore directly compared the senolytic capacity of ABT-263, quercetin, danazol, and nicotinamide riboside in human MSCs during long-term culture.

The effects of these compounds were analysed during long-term expansion of MSCs, until replicative senescence. Furthermore, we determined the effect on molecular markers for replicative senescence, such as senescence-associated beta-galactosidase staining (SA-β-gal), telomere attrition, and senescence-associated DNA methylation changes. Experiments revealed that ABT-263 had a significant but moderate senolytic effect. This was in line with reduced SA-β-gal staining in senescent MSCs upon treatment with ABT-263. However, none of the drugs had significant effects on the maximum number of population doublings, telomere length, or epigenetic senescence predictions. Of the four tested drugs, only ABT-263 revealed a senolytic effect in human MSCs - and even treatment with this compound did not rejuvenate MSCs with regard to telomere length or epigenetic senescence signature. It will be important to identify more potent senolytic drugs to meet the high hopes for regenerative medicine.

Link: https://doi.org/10.1186/s13287-018-0857-6

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